Tang Yuan, Li Hao-Yue, Wei Li-Chun, Li Ning, Zhang Wen-Jue, Lu Yu-Fei, Deng Fei-Yan, Xu Tong-Zhen, Shuai Jia-Cheng, Lei Zi-Fa, Meng Xian-Yu, Qi Shu-Nan, Song Yong-Wen, Zhang Wen-Wen, Jing Hao, Li Gong, Liu Shi-Xin, Wang Ying-Jie, Liu Zheng, Ma Hui-Ying, Wang Ning-Yu, Chen Bo, Wang Shu-Lian, Li Ye-Xiong, Zhao Li-Na, Tang Jian-Qiang, Jiang Zheng, Chen Ying-Gang, Zhou Hai-Tao, Hu Chen, Jin Jing
State Key Laboratory of Molecular Oncology and Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Department of Radiation Oncology, Xijing Hospital, Air Force Medical University, Xi'an, China.
Med. 2025 Aug 21:100807. doi: 10.1016/j.medj.2025.100807.
The therapeutic efficacy and mode of combining immunotherapy with neoadjuvant chemoradiotherapy in proficient mismatch repair (pMMR)/microsatellite stable (MSS) locally advanced rectal cancer (LARC) remain uncertain.
In this multicenter, randomized, seamless phase 2/3 trial (ClinicalTrials.gov: NCT05484024), eligible participants were randomly assigned (1:1) to receive short-course radiotherapy (SCRT) (5 Gy × 5), followed by 4 cycles of capecitabine and oxaliplatin or 6 cycles of leucovorin, oxaliplatin, and fluorouracil, with (iTNT group) or without (total neoadjuvant therapy [TNT] group) 4 cycles of sintilimab. Following neoadjuvant therapy, participants underwent surgery or a watch-and-wait strategy based on clinical complete response. The primary endpoints were the complete response (CR) rate for phase 2 and the 3-year disease-free survival (DFS) rate for phase 3.
218 patients were randomized to the iTNT group (n = 110) and the TNT group (n = 108). All patients completed SCRT, with 88.2% in the iTNT group and 93.5% in the TNT group completing 4 cycles of neoadjuvant treatment. The CR rate was significantly higher in the iTNT group (45.5% vs. 25.0%; p = 0.003). Grade 3-4 treatment-related adverse events were reported in 34.5% of the iTNT group and 19.4% of the TNT group (p = 0.012), with thrombocytopenia, diarrhea, leukopenia, and neutropenia being the most frequently observed. Grade 3-4 immune-related adverse events occurred in 5.5% of patients in the iTNT group.
The addition of the PD-1 inhibitor sintilimab significantly enhances the CR rate compared to SCRT-based TNT, with favorable tolerability in patients with pMMR/MSS LARC.
This work was funded by the National Natural Science Foundation of China (82473248) and the Shenzhen Medical Research Fund (C2301001).
在错配修复功能正常（pMMR）/微卫星稳定（MSS）的局部晚期直肠癌（LARC）中，免疫治疗与新辅助放化疗联合应用的疗效和模式仍不明确。
在这项多中心、随机、无缝2/3期试验（ClinicalTrials.gov：NCT05484024）中，符合条件的参与者被随机分配（1:1）接受短程放疗（SCRT）（5 Gy×5），随后进行4个周期的卡培他滨和奥沙利铂治疗，或6个周期的亚叶酸钙、奥沙利铂和氟尿嘧啶治疗，同时（免疫新辅助治疗组）或不（全新辅助治疗组）联合4个周期的信迪利单抗治疗。新辅助治疗后，参与者根据临床完全缓解情况接受手术或观察等待策略。主要终点是2期的完全缓解（CR）率和3期的3年无病生存率（DFS）。
218例患者被随机分配至免疫新辅助治疗组（n = 110）和全新辅助治疗组（n = 108）。所有患者均完成了SCRT，免疫新辅助治疗组88.2%的患者和全新辅助治疗组93.5%的患者完成了4个周期的新辅助治疗。免疫新辅助治疗组的CR率显著更高（45.5%对25.0%；p = 0.003）。免疫新辅助治疗组34.5%的患者和全新辅助治疗组19.4%的患者报告了3-4级治疗相关不良事件（p = 0.012），血小板减少、腹泻、白细胞减少和中性粒细胞减少是最常见的。免疫新辅助治疗组5.5%的患者发生了3-4级免疫相关不良事件。
与基于SCRT的全新辅助治疗相比，添加PD-1抑制剂信迪利单抗显著提高了CR率，且pMMR/MSS LARC患者耐受性良好。
本研究由中国国家自然科学基金（82473248）和深圳市医学科研基金（C2301001）资助。
